CN114478525B - Tetrahydro-beta-carboline pyrazole amide derivative and preparation method and application thereof - Google Patents
Tetrahydro-beta-carboline pyrazole amide derivative and preparation method and application thereof Download PDFInfo
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- carboline
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- pyrazole
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- -1 Tetrahydro-beta-carboline pyrazole amide Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims description 28
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 17
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 150000003217 pyrazoles Chemical class 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- 241000196324 Embryophyta Species 0.000 abstract description 9
- 235000007688 Lycopersicon esculentum Nutrition 0.000 abstract description 6
- 241000233679 Peronosporaceae Species 0.000 abstract description 6
- 241000123650 Botrytis cinerea Species 0.000 abstract description 3
- 241001290235 Ceratobasidium cereale Species 0.000 abstract description 3
- 241000813090 Rhizoctonia solani Species 0.000 abstract description 3
- 241000221696 Sclerotinia sclerotiorum Species 0.000 abstract description 3
- 240000003768 Solanum lycopersicum Species 0.000 abstract 1
- 201000010099 disease Diseases 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 244000000004 fungal plant pathogen Species 0.000 description 7
- 238000011835 investigation Methods 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 241000227653 Lycopersicon Species 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 4
- 240000008067 Cucumis sativus Species 0.000 description 4
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 241000233866 Fungi Species 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical group N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000006823 (C1-C6) acyl group Chemical group 0.000 description 1
- BADSZRMNXWLUKO-UHFFFAOYSA-N 4-chloro-1h-pyrazole Chemical compound ClC=1C=NNC=1 BADSZRMNXWLUKO-UHFFFAOYSA-N 0.000 description 1
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 1
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 1
- OEDUIFSDODUDRK-UHFFFAOYSA-N 5-phenyl-1h-pyrazole Chemical compound N1N=CC=C1C1=CC=CC=C1 OEDUIFSDODUDRK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HXYXTCJDWHHCBW-UHFFFAOYSA-N acetonitrile;toluene Chemical compound CC#N.CC1=CC=CC=C1 HXYXTCJDWHHCBW-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000007514 bases Chemical group 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 1
- MSPOSRHJXMILNK-UHFFFAOYSA-N ethyl 1h-pyrazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=NN1 MSPOSRHJXMILNK-UHFFFAOYSA-N 0.000 description 1
- RIKMMFOAQPJVMX-UHFFFAOYSA-N fomepizole Chemical compound CC=1C=NNC=1 RIKMMFOAQPJVMX-UHFFFAOYSA-N 0.000 description 1
- 229960004285 fomepizole Drugs 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000003032 phytopathogenic effect Effects 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a tetrahydro-beta carboline pyrazole amide derivative, which has a structure shown in a formula I. The invention provides a series of amide compounds with novel structures, which have higher antibacterial activity, in particular to the bactericidal activity of rhizoctonia solani, rhizoctonia cerealis, sclerotinia sclerotiorum, botrytis cinerea, downy mildew of tomato and the like, and have market application prospect as plant antibacterial agents.
Description
Technical Field
The invention relates to the technical field of pesticides, in particular to a tetrahydro-beta-carboline pyrazole amide derivative, and a preparation method and application thereof.
Background
Plant diseases have an adverse effect on plant growth, and it is important to control plant diseases caused by plant pathogenic fungi. Bactericides can solve plant diseases to some extent, however, the types of bactericides are newer slowly, and some bactericides develop resistance quickly.
The Chinese patent with the application publication number of CN101020688 discloses a derivative containing a tetrahydro-beta carboline skeleton, which has antibacterial activity, but has harsh reaction conditions and is not easy to produce and convert.
It is therefore of great importance to develop new compounds which are more potent, more economical, less toxic or have different sites of action.
Disclosure of Invention
In order to solve the problems, the invention provides a tetrahydro-beta carboline pyrazole amide derivative, a preparation method and application thereof, and the prepared tetrahydro-beta carboline pyrazole amide derivative has higher antibacterial activity.
The invention provides a tetrahydro-beta carboline pyrazole amide derivative, which has a structure shown in a formula I:
wherein R is 1 、R 3 Independently selected from one or more of H, halogen, C1-C6 alkyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, hydroxyl, ester, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, halogen-containing substituted phenyl and pyridyl;
R 2 is benzyloxy, methoxy;
R 4 selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy;
R 5 selected from H, C-C6 alkyl, C1-C6 formate, C1-C6 acetate, C1-C6 acyl;
x is O or S;
n is an integer of 1 to 3;
m is an integer of 1 to 4;
q is 1 or 2.
Wherein the R is 1 Preferably H, halogen, C1-C6 alkyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, hydroxy, ester, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl, halogen-containing substituted phenyl or pyridyl; more preferably H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, ester group, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl or halogen-containing substituted phenyl; further preferred is H, F, cl, br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, phenyl or ethoxycarbonyl.
As a preferred embodiment, the tetrahydro- β carboline pyrazole amide derivative of the present invention has any one of the compounds shown in table 1 of the general formula i.
TABLE 1
Preferably, the R 1 Is substituted in the 3-or 4-position.
The R is 2 Preferably benzyloxy and methoxy.
Preferably, said R 3 、R 4 、R 5 All are H.
Preferably, X is O.
Preferably, n, m and q are all 1.
Preferably, the tetrahydro-beta carboline pyrazole amide derivative has any one of the following structures:
the invention also provides a preparation method of the tetrahydro-beta carboline pyrazole amide derivative, which comprises the following steps:
and mixing the tetrahydro-beta carboline amide and the pyrazole derivatives in a solvent, and reacting under the action of an acid binding agent and thionyl chloride to obtain the tetrahydro-beta carboline pyrazole amide derivatives.
The solvent is preferably one or more of toluene, xylene, dichloromethane, dichloroethane, methyl tert-butyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, ethyl acetate and acetonitrile; toluene is more preferred.
The acid binding agent is preferably a basic compound.
The alkaline compound is preferably one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine and pyridine; more preferably triethylamine.
The temperature of the reaction is preferably 5-70 ℃; more preferably 5 to 10 ℃.
Preferably, the preparation method specifically comprises the following steps:
s1) mixing tetrahydro-beta carboline amide and pyrazole derivatives in a solvent, and reacting under the action of an acid binding agent and thionyl chloride;
s2) after the reaction is finished, regulating the pH value of the system to 1-2, and separating to obtain an organic phase;
and S3) drying and purifying the organic phase to obtain the tetrahydro-beta carboline pyrazole amide derivative.
Preferably, the thionyl chloride is added in a dropwise manner.
The temperature of dropwise adding thionyl chloride is preferably-10-20 ℃; more preferably 5 to 10 ℃.
The purification mode of the present invention is not particularly limited, and may be a purification mode known to those skilled in the art, such as recrystallization, column chromatography, etc., and the present invention preferably employs a column chromatography, and the eluent for the column chromatography is preferably an ethyl acetate-petroleum ether system.
The invention also provides application of the tetrahydro-beta carboline pyrazole amide derivative or the tetrahydro-beta carboline pyrazole amide derivative prepared by the preparation method as an active ingredient of an antibacterial agent.
The invention also provides an antibacterial agent, which comprises the tetrahydro-beta carboline pyrazole amide derivative or the tetrahydro-beta carboline pyrazole amide derivative prepared by the preparation method.
In the invention, the tetrahydro-beta carboline pyrazole amide derivative can be used as the only active ingredient or used in combination with other antibacterial agents or antiviral agents.
Compared with the prior art, the invention provides a tetrahydro-beta carboline pyrazole amide derivative which has a structure shown in a formula I. The invention provides a series of amide compounds with novel structures, which have higher antibacterial activity, in particular to rhizoctonia solani, rhizoctonia cerealis, sclerotinia sclerotiorum, botrytis cinerea and downy mildew of tomato, and have remarkable bactericidal activity and good market application prospect as plant antibacterial agents.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 1;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of compound 3;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of compound 7.
Detailed Description
In order to further illustrate the invention, the following describes the tetrahydro-beta carboline pyrazole amide derivative, the preparation method and the application thereof in detail by combining the examples.
Example 1 preparation of Compound 1
Tetrahydro-beta carboline monoamide (19 g) was added to a 500ml three-necked flask, then anhydrous toluene (190 ml) was added, pyrazole (3.55 g) was added under stirring, and stirring was maintained at a temperature of 5-10℃for 10min. Then adding triethylamine (17.57 g), stirring for 5min at the temperature, slowly dropwise adding thionyl chloride (6.2 g) into the system, after the completion of the dropwise adding, keeping the temperature at 5-10 ℃ for reaction for 12h, adding water into the system after the completion of the central control of the reaction, acidifying to pH=1-2, separating out an organic layer, washing the organic layer for three times, drying by anhydrous sodium sulfate, and separating by column chromatography (ethyl acetate: petroleum ether=1:3) to obtain the compound 1.
1 H NMR(400MHz,DMSO-d 6 ):δ11.00-11.05(d,1H),8.35(s,1H),7.99-8.01(d,1H),7.29-7.45(m,7H),7.05-7.08(t,1H),6.94-6.97(t,1H),6.65(s,lH),6.43-6.45(dd,1H),5.15-5.29(m,3H),3.26-3.38(m,2H),1.64-1.72(dd,3H)。
The nuclear magnetic hydrogen spectrum of the compound 1 is shown in figure 1.
Example 2 preparation of Compound 2
The preparation method of the compound 2 is the same as that of the compound 1, and pyrazole is replaced by 4-chloropyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.94-11.02(d,1H),8.40(s,1H),7.97-8.05(m,2H),7.14-7.54(m,6H),7.04-7.07(t,1H),6.93-6.96(t,1H),6.48-6.58(d,1H),5.17-5.28(m,3H),3.31-3.04(m,2H),1.57-1.59(dd,3H)。
EXAMPLE 3 preparation of Compound 3
The preparation method of the compound 3 is the same as that of the compound 1, and pyrazole is replaced by 4-methylpyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ11.00-11.06(d,1H),8.08(s,1H),7.82-7.85(d,1H),7.29-7.44(m,7H),7.05-7.08(t,1H),6.94-6.97(t,1H),6.41-6.42(d,1H),5.15-5.29(m,3H),3.23-3.36(m,2H),2.06(s,3H),1.67-1.74(dd,3H)。
The nuclear magnetic hydrogen spectrum of the compound 3 is shown in fig. 2.
EXAMPLE 4 preparation of Compound 4
The preparation method of the compound 4 is the same as that of the compound 1, and pyrazole is replaced by 3-methylpyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.99-11.04(d,1H),8.22(s,1H),7.30-7.44(m,7H),7.05-7.08(t,1H),6.94-6.97(t,1H),6.39-6.48(d,2H),5.18-5.27(m,3H),3.27-3.35(m,2H),2.31-2.42(m,3H),1.65-1.74(dd,3H)。
EXAMPLE 5 preparation of Compound 5
The preparation method of the compound 5 is the same as that of the compound 1, and pyrazole is replaced by 3-phenylpyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.97-11.05(d,1H),8.40(s,1H),7.99-8.06(m,2H),7.18-7.54(m,11H),7.06-7.09(t,1H),6.94-6.97(t,1H),6.51-6.58(dd,1H),5.19-5.30(m,3H),3.35-3.42(m,2H),1.61-1.62(d,3H)。
EXAMPLE 6 preparation of Compound 6
The preparation method of the compound 6 is the same as that of the compound 1, and pyrazole is replaced by 3-trifluoromethyl pyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.98-11.02(d,1H),8.59-8.61(d,1H),7.30-7.43(m,7H),7.13-7.14(d,1H),7.06-7.09(t,1H),6.95-6.98(t,1H),6.40(s,1H),5.12-5.28(m,3H),3.28-3.29(d,2H),1.47-1.58(dd,3H)。
EXAMPLE 7 preparation of Compound 7
The preparation method of the compound 7 is the same as that of the compound 1, and pyrazole is replaced by 3-ethoxycarbonyl pyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.99-11.01(d,1H),8.45-8.48(d,1H),7.29-7.43(m,7H),7.01-7.08(m,2H),6.95-6.96(d,1H),6.43(s,1H),5.21-5.25(d,3H),4.37-4.38(d,2H),3.23-3.38(m,2H),1.50-1.68(dd,3H),1.31-1.36(m,3H)。
The nuclear magnetic resonance hydrogen spectrum of the compound 7 is shown in fig. 3.
EXAMPLE 8 preparation of Compound 8
The preparation method of the compound 8 is the same as that of the compound 1, and pyrazole is replaced by 4-ethoxycarbonyl pyrazole.
1 H NMR(400MHz,DMSO-d 6 ):δ10.98-11.01(d,1H),8.75-8.81(d,1H),8.27-8.32(d,1H),7.30-7.43(m,7H),7.05-7.08(t,1H),6.94-6.97(t,1H),6.40(s,1H),5.15-5.28(m,3H),4.25-4.29(q,2H),3.24-3.36(m,2H),1.57-1.65(dd,3H),1.27-1.30(t,3H)。
The compounds shown in table 2 were prepared according to the scheme above:
TABLE 2
Example 9 determination of bactericidal Activity
The bactericidal activity of the tetrahydro-beta carboline pyrazole amide derivative compound prepared by the invention on plant pathogenic fungi is measured
1. Test plant pathogenic fungi
Rhizoctonia solani, rhizoctonia cerealis, and Sclerotinia sclerotiorum.
2. Indoor experiment method
The relative inhibition rate of hypha is measured by a toxic culture medium method:
firstly, diluting a tetrahydro-beta carboline pyrazole amide derivative compound with sterile water, then uniformly mixing the diluted compound with a PDA culture medium, and preparing a series of drug-containing plates with uniform thickness by adopting a double dilution method at the final concentration of the tetrahydro-beta carboline pyrazole amide derivative compound, wherein sterile water is used as a blank control, and each treatment is repeated for 3 times. After the culture medium is solidified, inoculating a test fungus cake of plant pathogenic fungi on the solidified culture medium, culturing for 3-5 days at 27-28 ℃, measuring the colony diameter by a crisscross method, and calculating the hypha growth inhibition rate, wherein the fungus cake diameter is 0.4 cm.
3. Experimental results
The determination results of the inhibitory activity of the tetrahydro-beta carboline pyrazole amide derivative compounds on plant pathogenic fungi are shown in table 3.
Table 3 relative inhibition of the phytopathogenic fungi of Compounds 1 to 16 at 20mg/L (%)
As shown in Table 3, the tetrahydro-beta carboline pyrazole amide derivative compound prepared by the invention has good inhibitory activity on plant pathogenic fungi at 20mg/L, is expected to be developed into a novel efficient green chemical pesticide, and has wide market application prospect.
4. Field efficacy experiment method
4.1 field efficacy test of different Compounds for controlling Botrytis cinerea of cucumber
4.11 test sites, methods of treatment and dosage
Test site: cao Wanglu Liu Cun in Boxing county; when the liquid medicine is prepared, a small amount of water is used for dissolving the medicament with the required amount for each treatment, and then water is added to the required water amount for each treatment concentration for uniform spraying. Compounds 1 to 16 were used for controlling cucumber gray mold by adding 10g of water 15L each.
4.12 investigation method
Five samples were taken per cell, 2 plants were investigated per spot, all leaves and all fruits of each plant were investigated, the disease-fruit rate was calculated and recorded separately according to the following classification method.
Leaf damage classification method (taking leaf as unit):
level 0: no disease spots;
stage 1:3 disease spots are arranged on a single leaf;
3 stages: single leaf with disease spots
5 stages: single leaf with disease spots
7 stages: the single leaf has 11-20 disease spots, and part of the single leaf is densely packed into a sheet;
stage 9: the single leaf has more than one quarter of densely-occupied disease spots.
4.13 investigation time and times
The disease cardinal number survey was performed prior to administration, two times, and the last survey was performed 10 days after the last administration.
4.14 method for calculating efficacy
The drug effect is calculated according to the formulas (1) and (2);
control effect (%) = (1- (ck0×pt1)/(ck1×pt0))×100 … … … (2)
Wherein: CK 0-index of disease prior to dosing in the placebo area;
CK 1-disease index after dosing in the placebo area;
PT 0-index of pre-dose condition in the dose treatment zone;
PT 1-disease index after administration in the agent treatment zone.
Table 4 control effect of Compounds 1 to 16 on cucumber gray mold at 10g/15L (%)
As shown in Table 4, the tetrahydro-beta carboline pyrazole amide derivative compound prepared by the invention has a strong control effect on cucumber gray mold at the dosage of 10 g/15L.
4.2 field efficacy test of different Compounds for controlling tomato downy mildew
4.21 test sites, methods of treatment and dosage
Test site: store town size Wang Cun; when the liquid medicine is prepared, a small amount of water is used for dissolving the medicament with the required amount for each treatment, and then water is added to the required water amount for each treatment concentration for uniform spraying. Compounds 1 to 16 were each used for controlling tomato downy mildew with 15g of water 15L.
4.22 investigation method
Four-point investigation is randomly carried out in each cell, two plants are investigated in each spot, and all the leaves are investigated in each plant.
Classification method (in leaf):
level 0: no disease spots;
stage 1: the area of the disease spots accounts for less than 5% of the whole leaf area;
3 stages: the area of the lesion occupying the whole leaf area
5 stages: the area of the lesion occupying the whole leaf area
7 stages: the area of the lesion occupying the whole leaf area
Stage 9: the area of the disease spots accounts for more than 50% of the whole leaf area.
4.23 investigation time and times
Disease number investigation was performed prior to administration, two times, and the last investigation was performed 10 days after the last administration.
4.24 method for calculating efficacy
The drug effect is calculated according to the formulas (1) and (2);
control effect (%) = (1- (ck0×pt1)/(ck1×pt0))×100 … … … (2)
Wherein: CK 0-index of disease prior to dosing in the placebo area;
CK 1-disease index after dosing in the placebo area;
PT 0-index of pre-dose condition in the dose treatment zone;
PT 1-disease index after administration in the agent treatment zone.
Table 5 control effect of Compounds 1 to 16 on tomato downy mildew at 15g/15L (%)
From Table 5, it is clear that the tetrahydro-beta carboline pyrazole amide derivative compound prepared by the invention has stronger control effect on tomato downy mildew at the dosage of 15 g/15L.
In conclusion, the tetrahydro-beta carboline pyrazole amide derivative compound prepared by the invention has good inhibitory activity on plant pathogenic fungi, is hopeful to be developed into a novel efficient green chemical pesticide, and has wide market application prospect.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (7)
1. A tetrahydro-beta carboline pyrazole amide derivative having the structure shown in formula i:
wherein R is 1 Independently selected from one or more of H, halogen, C1-C6 alkyl, C1-C6 alkoxycarbonyl, difluoromethyl, trifluoromethyl, phenyl and halogen-containing substituted phenyl;
the R is 1 Is substituted in the 3-or 4-position;
R 2 is benzyloxy, methoxy;
R 3 selected from H;
R 4 selected from H;
R 5 selected from H;
x is O;
n is 1;
m is 1;
q is 1.
2. The tetrahydro- β carboline pyrazole amide derivative according to claim 1, having any one of the following structures:
3. the process for the preparation of a tetrahydro- β carboline pyrazole amide derivative according to any one of claims 1 to 2, comprising the steps of:
and mixing the tetrahydro-beta carboline amide and the pyrazole derivatives in a solvent, and reacting under the action of an acid binding agent and thionyl chloride to obtain the tetrahydro-beta carboline pyrazole amide derivatives.
4. The method according to claim 3, wherein the solvent is one or more selected from toluene, xylene, methylene chloride, dichloroethane, methyl tertiary butyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, ethyl acetate, acetonitrile;
the acid binding agent is an alkaline compound;
the alkaline compound is selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine and pyridine;
the temperature of the reaction is 5-70 ℃.
5. A method of preparation according to claim 3, comprising the steps of:
s1) mixing tetrahydro-beta carboline amide and pyrazole derivatives in a solvent, and reacting under the action of an acid binding agent and thionyl chloride;
s2) after the reaction is finished, regulating the pH value of the system to 1-2, and separating to obtain an organic phase;
and S3) drying and purifying the organic phase to obtain the tetrahydro-beta carboline pyrazole amide derivative.
6. Use of a tetrahydro-beta carboline pyrazole amide derivative according to any one of claims 1 to 2 or a tetrahydro-beta carboline pyrazole amide derivative prepared by a preparation method according to any one of claims 3 to 5 as an active ingredient of an antibacterial agent.
7. An antibacterial agent comprising the tetrahydro- β carboline pyrazole amide derivative according to any one of claims 1 to 2 or the tetrahydro- β carboline pyrazole amide derivative prepared by the preparation method according to any one of claims 3 to 5.
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